Nat Commun - Early-life-trauma triggers interferon-β resistance and neurodegeneration in a MS model via down regulated β1-adrenergic signaling - Khaw

[Kalliope]

Nature Communications:
Early-life-trauma triggers interferon-β resistance and neurodegeneration in a multiple sclerosis model via downregulated β1-adrenergic signaling - Yee Ming Khaw et al


Abstract
Environmental triggers have important functions in multiple sclerosis (MS) susceptibility, phenotype, and trajectory.

Exposure to early life trauma (ELT) has been associated with higher relapse rates in MS patients; however, the underlying mechanisms are not well-defined.

Here we show ELT induces mechanistic and phenotypical alterations during experimental autoimmune encephalitis (EAE).

ELT sustains downregulation of immune cell adrenergic receptors, which can be attributed to chronic norepinephrine circulation. ELT-subjected mice exhibit interferon-β resistance and neurodegeneration driven by lymphotoxin and CXCR2 involvement.

These phenotypic changes are observed in control EAE mice treated with β1 adrenergic receptor antagonist.

Conversely, β1 adrenergic receptor agonist treatment to ELT mice abrogates phenotype changes via restoration of immune cell β1 adrenergic receptor function.

Our results indicate that ELT alters EAE phenotype via downregulation of β1 adrenergic signaling in immune cells.

These results have implications for the effect of environmental factors in provoking disease heterogeneity and might enable prediction of long-term outcomes in MS.

 

[cassava7]

In mice.

ETA, from the methods:

ELT [Early-life-trauma] model
We created an ELT model by subjecting mouse pups to maternal separation with PBS [phosphate-buffered saline] injections. First, mouse pups were separated daily from their mother and father (3–6 months old) for 3 h (3–6 pm) during postnatal days 2–14. Newborn mice share their cage with parents until wean time. Neonates subjected to ELT or no neonatal treatment were derived from different litters. To induce physical stress, intraperitoneal injections of 40 μL PBS were administered to pups with a 27G needle during postnatal days 4–10 while they were separated from their mother as an additional stressor. During separation, pups were kept together in a dark covered cage with supplemental heat to avoid pup abandonment due to low body temperature. Normal parental care-taking behavior was observed after reunification despite the intervention. Pups were weaned from their mothers on postnatal day 28.

Not only is this horrible but it is also a completely unrealistic model for humans...

I don't know exactly at what age the incidence of MS is highest (not accounting for premonitory symptoms appearing earlier in life) but most people seem to be diagnosed between their 20's and 40's, except for late-onset MS. How do 30 days compare with (a mean of) 30 years in this model?

Similarly:

 

[Kalliope]

A Norwegian news site about research has an article today about this study.

Khaw and colleagues took some of the mice away from their mother for several days while they were young, and also gave them injections of saline. This is how they inflicted both mental and physical stress on the mice.

...

The results showed that the mice that had had bad experiences more easily developed EAE. They also more often had long-term paralysis and major damage to the nervous system.

In addition, these mice often had little effect on beta-interferon, one of the most widely used anti-ME drugs.

The researchers linked the differences to physical changes in the mice's bodies.

The bad experiences seemed to lead to changes in certain parts of the immune system.

...

However, it is worth remembering that a study on mice can not say anything certain about what is going on in humans. Previous studies on bad experiences and health in humans have pointed in different directions.

Forskning.no Vonde opplevelser gjorde mus mer utsatt for MS
google translation: Bad experiences made mice more prone to MS

I feel awful for the mice

 

[Hoopoe]

Childhood trauma or early-life trauma (ELT), characterized by events such as emotional neglect or physical abuse, increases MS susceptibility later in life along with MS relapse rates and likelihood of MS-related hospitalization11,12

The claim is questionable since both of these are retrospective studies.
https://pubmed.ncbi.nlm.nih.gov/19188532/
https://pubmed.ncbi.nlm.nih.gov/22408134/

They may simply be measuring the effect of illness severity on the current mood of patients which can influence how past events are rated.

 

[Mithriel]

It leaves out the most important question. Many children experience early life trauma but do not get MS so the question of why some people get MS and others don't is still wide open.

Also MS is commoner in higher latitudes yet if early trauma was a cause you would expect it to be highest in refugee camps, say.

In the MS therapy centre I have attended for 25 years, I can only remember 2 non white patients and they were Pakistani and had lived here since childhood. It is not any kind of racism, many of the therapists over the years have not been white and neither have the doctors who send people there.

Early life experiences do not divide along racial lines so they cannot be terribly important.

 

[Hutan]

Also MS is commoner in higher latitudes yet if early trauma was a cause you would expect it to be highest in refugee camps, say.

Yes, the idea doesn't hold up as being among the most important factors when you look at the epidemiological evidence. MS is common in New Zealand relative to the rest of the world, and yet life in New Zealand is generally far less traumatic than in many countries with much lower rates of the disease.

It could be argued, with much evidence, that there is, on average, more trauma in the lives of Maori children than in non-Maori children in New Zealand. Many Maori families experience relative poverty and the difficulties that flow from that as a long-standing consequence of colonisation. And yet:

The prevalence of MS in New Zealand in 2006 was 73.2 (age standardized per 100,000) while for those with indigenous Māori ancestry it was 3.6 times lower at 20.6.

While less good access to medical care (on average) might delay diagnosis in Maori, there is universal, essentially free, health care, so that idea can not account for such a big difference. Time to diagnosis was not found to be different in the study I'm looking at.

there were no significant differences in clinical characteristics between Māori and the national MS cohort

This suggests that the disease does not look different once established either, despite likely differences in rates of early trauma.

 

[rvallee]

The amount of assumptions here is excessive. So many confounding factors and a very bizarre concept of trauma.